Today’s New York Times features an op-ed by Dr. Ezekiel Emanuel, on the oncology drug shortage. It’s a serious problem that’s had too-little attention in the press:

Of the 34 generic cancer drugs on the market, as of this month, 14 were in short supply. They include drugs that are the mainstay of treatment regimens used to cure leukemia, lymphoma and testicular cancer.

Emanuel considers that these cancer drug shortages have led to what amounts to an accidental rationing of cancer meds. Some desperate and/or influential patients (or doctors or hospitals) get their planned chemo and the rest, well, don’t.

Unfortunately, what’s behind this harmful mess is neither a dearth of ingredients nor unsolvable problems at most of the manufacturing plants. Rather, the missing chemotherapies are mainly old and inexpensive, beyond their patent protection, i.e. they’re not so profitable, and not high-priority.

Emanuel proposes that the prices of old oncology meds – drugs that can cost as little as $3 per dose – be raised so that the companies will make it their business to provide them. This seems like a reasonable idea, although I find it a bit too compromising. Why should we raise the costs of any medications above what’s necessary for their manufacture and distribution?

The underlying problem is that we rely on a profit motive to deliver needed health care in the U.S. This kind of financial incentive, even if you find it morally acceptable, doesn’t seem to be working.

That’s why I favor scrapping the system – in which insurance companies siphon off some 30 percent or so of expenses, and pharmaceutical companies take another big cut – and giving patients the care they need, profits aside.

This point follows closely from the previous, that doctors need to talk with patients earlier on end-of-life issues. But the central issue here is that most patients with cancer are unrealistic about their prognosis, and that oncologists do a terrible job in correcting their misperceptions:

…According to one recent study, most of the patients with lung cancer expected to live for more than 2 years even though the average length of survival is about 8 months.3

Resetting expectations will be difficult. Tools are available to help the oncologist provide truly informed consent by sharing anticipated response rates, chances of cure (always near zero for patients with metastatic solid tumors), and side effects…Many oncologists do not have these skills,43 so use of a decision aid may help…

What they’re describing amounts to Lake Wobegon effect, from the patient’s perspective, and that may be fair enough.

But I think these authors are letting oncologists off easy. Why it is that they lack “these skills,” i.e. what it takes to help patients face reality? It happens yesterday I was reading Dave deBronkart’s book, How to Laugh, Sing and Eat Like a Pig, on his experiences as a patient with metastatic kidney cancer, and he cites a terrific, pertinent excerpt in Dr. Jerome Groopman’s The Anatomy of Hope:

Hope, unlike optimism, is rooted in unalloyed reality. …Hope acknowledges the significant obstacles and deep pitfalls along the path. True hope has no room for delusion.

Clear-eyed, hope gives us the courage to confront our circumstances and the capacity to surmount them. For all my patients, hope, true hope, has proved as important as any medication.

I don’t think oncologists need (or better, should need) decision aids to help them reset patients’ unrealistic expectations. What they need is time, and thoughtfulness, and the capacity to be genuinely empathic.

If our health care system promoted trusting, and ideally longer, relationships of cancer patients with their physicians, patients would be less fearful of hearing the truth, and their doctors would be less afraid to speak honestly with them. This would reduce cancer care costs by lessening futile treatments, and would improve the quality of the patient-doctor relationships in oncology, besides the quality of care, in itself, and patients’ experiences as they near the end of life.

In other words (theirs): “The first step is a frank acknowledgment that changes are needed.” A bit AA-ish, but fair enough –

The authors talk about needed, frank discussions between doctors and patients. They emphasize that oncologists/docs drive up costs and provide poorer care by failing to talk with patients about the possibility of death, end-of-life care, and transitions in the focus of care from curative intent to palliation.

They review published findings on the topic:

In a study at our institution of 75 hospitalized patients with cancer, the oncologist had initiated a discussion of advance directives with only 2 patients.31 In a prospective, multicenter study of 360 patients, only 37% of the patients and their families could recall having a discussion about impending death with the physician.32 Such a discussion is a prerequisite to good planning. Oncologists wait until symptoms appear or until they believe that nothing more can be done.33 In one study, at 2 months before their death, half the patients with metastatic lung cancer had not had a discussion with their doctors about hospice.34 This may explain why in a recent series the average length of stay in hospice for patients with lung cancer was 4 days.35

Although I have questions about the specific methods for some of these references, the bottom line is clear: Oncologists wait too long to talk with their patients about palliative or hospice care.

What they’re saying is that doctors need to get a grip on the problem (to overcome their denial and inability to talk about death), if they want to help patients come to terms with the inevitable. Doing so would save billions each year in the US, and would also spare patients from futile treatments and needless suffering.

I couldn’t agree more. It’s a potential win/win, if physicians think realistically about the situation and possible outcomes, and speak openly – and gently, no matter what, with their patients.

Giving one drug or combination regimen, and then another, and another, and another, to cancer patients whose tumors resist multiple regimens is more likely to cause harm than good. Oncologists need be realistic with themselves and with their patients, in a kindly way, when treatments fail.

Options to consider, besides chemo, include palliation (which can be started at any time, including before and during chemotherapy), alternative approaches (such as hormonal or immune-based therapy, for some tumors), hospice care and participation in a clinical trial, as the authors suggest, based on the patient’s condition and preferences.

In this section, the authors allude to what I think might be a cost-saving advance in oncology practice: why not make available lower doses of white blood cell (WBC) colony stimulating factors?

The issue is this: when people get high doses of chemotherapy, they’re compromised because the bone marrow doesn’t create new WBCs as it should. The risk of infection during chemo used to be so great that, in the 1980s and earlier, it was common for cancer patients to succumb to infection. With the advent of WBC stimulants in the early 1990s, the risks of infection during chemo dropped markedly.

These are complex and expensive drugs. And while I agree with the NEJMauthors that chemotherapy is over-used, often, I don’t think it makes sense to cut down on potentially helpful doses or combinations of those drugs just because WBC stimulants are expensive.

Take Neulasta (pegfilgrastim), a long- acting stimulator of neutrophils manufactured by Amgen. This injectible drug costs over $ 2,000 for a single, 6 milligram vial. It’s supposed to be given every 2 weeks, although some oncologists might give it at a lesser frequency, depending on the chemo cycles. There’s only one size dose available for all patients; they’re all billed for the full 6 milligrams.

This is an ideal situation for Amgen, which takes in over $2000 for each 6 milligram vial. It’s far from perfect for patients who, even if there’s no toxicity, pay huge co-pays with each chemo cycle.

You can find some patients’ discussions of this issue at cancer support sites likethese. There’s also a public correspondence between Medicare and the State of Wisconsin on the high costs of this drug.

Around 10 years ago, when I was practicing, I wondered why we couldn’t give some patients less than 6 milligrams of Neulasta. This would be useful in at least three situations: for patients who are physically small; for those who receive lower doses of chemo; and for people who are hyper-sensitive, for whom just a tiny bit is enough to raise the white count adequately. A frequent toxicity is bone pain; this is intense in some patients and, in theory, would be less problematic if a lower dose were available. Once, I almost got into administrative trouble for asking a pharmacist to draw up only half of the dose from a vial so that I might give a petite woman only 3 milligrams of this powerful drug.

Since then, nothing’s changed. I looked it up yesterday; there’s still only one dose of Neulasta: 6 milligrams.

So if Neulasta were sold in lower-dose vials, like 1, 2, 3 or 4 milligrams, patients could receive lesser doses, as is often appropriate. The costs of these drugs, when administered properly, might be halved, approximately, without compromising on recommended doses of chemotherapy.

What they’re suggesting is a simple rule: “Patients must be well enough to walk unaided into the clinic to receive chemotherapy.” There are necessary exceptions, they point out, such as cancer patients disabled by another medical condition but who otherwise can carry out daily activities with relative normalcy. (I’ll offer an example: say a 50-year woman with multiple sclerosis who is wheel-chair bound but otherwise essentially well; she would be a candidate for treatment in this scenario.) But in general the authors would hold off on chemotherapy for cancer patients with a limited performance status – a measure that oncologists use to assess how well, or disabled, a person is in their capacity to work, perform ordinary daily activities and care for him or herself.

I’m not sure I agree with the “walking” threshold, or ECOGperformance status 3 or below, as the authors describe: “meaning that they are capable of only limited self-care and are confined to a bed or chair more than 50% of waking hours.” These criteria are subjective and problematic. But I do think the authors are onto a central, unavoidable issue in reducing health care costs. That is by limiting care, i.e. by rationing.

For elderly patients with cancer, especially for those who have significant other illnesses, it may not be appropriate for doctors to give chemotherapy and other, non-palliative cancer treatments. The authors don’t (dare) advise a particular age cut-off for therapy; they suggest using performance status criteria. They conclude this section of the paper on cutting cancer care costs with this statement: “Implementation of such a simple threshold could dramatically decrease the use of chemotherapy at the end of life.”

The authors are right, that we (oncologists and other doctors) shouldn’t be in the business of routinely giving aggressive treatments to patients who are very old and frail, who are more likely to suffer harms of treatment than potential benefits. Not just because we can’t continue driving up U.S. health care costs indiscriminately, but because when very frail, elderly patients are given chemotherapy they’re less likely to recover after treatment. By not saying “no” to patients who are too fragile for a requested intervention, or by simply treating patients who are so feeble or demented, or both, that they’re unable to say “no” for themselves – such as sometimes happens in nursing homes and other chronic care facilities, doctors may cause more harm than good.

Some readers of this blog may be wondering how I can reconcile this position with what I’ve said about access to Avastin for women with advanced BC. In my opinion, patients’ age and, broadly, their functionality – if they can think and communicate seems at least as relevant as whether they can walk – should be factored into the risk/potential benefits analysis of almost any medical treatment.

So if we’re going to consider restricting cancer drugs and interventions based on cost, indirectly or overtly, we should account for patients’ ages, the potential length and quality of life to be gained: If there’s a 50 year old patient who might benefit from a costly cancer treatment, it’s likely that person will benefit more from that drug than would a 70 year old patient, or a 90 year old patient. It’s also more likely, but not a sure thing, that a younger, otherwise healthier patient will tolerate a given treatment with fewer side effects.

A Cochrane meta-analysis showed that combination therapy had a small advantage over single agents for first-line therapy but caused more toxicity, and the review left unresolved the question of whether sequential single agents were a better choice.

…patients will live just as long but will avoid toxic effects. Second, society will benefit from cost reductions associated with less chemotherapy, fewer supportive drugs, and fewer toxicity-associated hospitalizations.

This approach is tempting, cost-wise, but may be simplistic: The purpose of combination chemotherapy is to give agents that work additively or synergistically, typically each at a lower dose, to achieve more effective treatment. In cancer, the best-studied multidrug regimens are in lymphoma, leukemia and breast cancer. Similar principles apply to antibiotic regimens for some infectious diseases, such as the drug “cocktails” for HIV or tuberculosis.

It could be that the authors are right for certain agents and some tumor types. But, likely, some drugs, including new targeted treatments given to patients who’ve already had several treatments, may be most effective and, paradoxically, less toxic – because the dose of each drug can be lower. The likelihood of resistant clones emerging may be diminished, too.

The problem we’re left with, of course, is that testing the different combination regimens will be costly. But I wouldn’t assume it’s better or necessarily cost-effective to give cancer drugs one at a time.

Yesterday’s post was not really about Avastin, but about medical journalism and how patients’ voices are handled by the media.

L. Husten, writing on a Forbes blog, cried that the press fawned, inappropriately, over patients’ words at the FDA hearing last week, and that led him to wonder why and if journalists should pay attention to what people with illness have to say, even if their words go against the prevailing medical wisdom.

There’s a fair amount of controversy on this. For sake of better discussion in the future, I think it best to break it up into 3 distinct but inter-related issues:

1. About health care journalism and patients’ voices:

A general problem I perceive (and part of why I started blogging) is how traditional medical journalists use patients’ stories to make a point. What some of my journalism professors tried to teach me, and most editors I’ve dealt with clearly want, is for the reporter to find a person with an illness, as a lead, and then tell about the relevant news, and provide some expert commentary – with at least one person speaking on each “side” of the issue, of course – and then end the story with some bit about the patient and the future.

I argue that this form of medical journalism reduces the patient to an object, used by the story-teller in order to capture the reader’s attention. So, with exceptions and always with the person’s consent, I prefer to offer my own story, from my perspective, so as not to use the patient as a vehicle or literary device.

So it appears that Husten is OK with using patients’ voices to tell a story (and sell papers/clicks?), but not with presenting their views unfiltered if they don’t mesh with the party line or a particular point an editor wants to make. This lies at the center of the journalism issue.

(As an aside, a few recent published studies have found value in analyses of patient-reported symptoms, unfiltered even by their doctors.)

2. About Avastin:

My impression is that some beast cancer advocates, including a National Breast Cancer Coalition representative who spoke at the FDA hearing, have chosen to “take the hit” on this particular issue because they need and want to appear rational. The straightforward-seeming argument is that the data show Avastin doesn’t work and is often harmful, so it shouldn’t be FDA-approved for women with metastatic BC. From the perspective of a BC advocacy group, it may not be worth pushing for a drug that helps only around 5% of patients.

The problem is there’s no biomarker for Avastin responsiveness, because this drug doesn’t target a particular genetic marker. Rather it works by cutting the blood supply, which could vary even within a particular patient’s mets in different organs. The only way to test if Avastin works in a patient is to give the drug, with informed consent, and see how it goes. Unlike, say, a bone marrow transplant, which runs in the range of hundreds of thousands of dollars and, once done, is irreversible, you can give one dose of Avastin and stop it, or two and stop it, if it doesn’t work or it is not well-tolerated.

Based on my experience as an oncologist and patient who’s received some risky interventions, I don’t think Avastin is more toxic than many or even most cancer drugs. Rather, its side effects have been heavily pushed by the media and public health/epidemiology academics in the past two years, who perhaps wish to make a larger point about this costly drug and evidence based medicine (EBM).

3. About evidence-based medicine: I’m in favor of EBM, especially in principle. The problem is that published medical data is too-often flawed and also, that some patients are, really, outliers.

My cousin testified before the FDA oncology advisory board on Tuesday about her experience taking Avastin. This is a tragedy, to deny the only drug that is keeping a 51 year old woman alive.

image from p.3 of today’s NYTimes business section

You have to wonder, are the advisory panel members so rational in all their behavior and choices? Are they always so razor-like in their oncology decisions?

Unlikely.

These experts have an agenda, here: It’s to be perceived as scientists, even when their knowledge is imperfect and exceptions to the rule stand right in front of their eyes. But clinical medicine calls for flexibility, and tailoring of treatment to each case, and caring about each person, including those who fall at the tail, or in this case better end, of any Kaplan-Meier survival curve.

What would Larry Kramer do about this, I’ve been thinking: He’d scream, really loud, so loud he might break his eardrums. He’d wonder why others, affected and near, aren’t doing the same. And he’d understand why this picture is on page 3 of the business section, and not on the front cover; it’s because people don’t want to look or see or know or think about it too much, because it hurts.

That is the normal heart, and this is a normal response to what’s happening to women with metastatic breast cancer.

This is the second in a series of posts on Bending the Cost Curve in Cancer Care. We should consider the proposal, published in the NEJM, gradually over the course of this summer, starting with “suggested changes in oncologists’ behavior,” #1:

The NEJM authors consider that after a cancer diagnosis many patients, understandably, seek reassurance that any recurrence will be detected early, if it happens. Doctors, for their part, may not fully appreciate the lack of benefit of detecting a liver met when it’s 2 cm rather than, say, just 1 cm in size. What’s more, physicians may have a conflict of interest, if they earn ancillary income by ordering lab and imaging tests.

My take:

It’s clear that some and possibly most cancer patients get too many and too frequent post-treatment surveillance tests. Believe it or not, yours truly, whose life was saved by a screening digital mammogram, maintains a healthy fear of excess radiation exposure. I agree to x-rays, CT scans, myelograms and whatever else my doctors suggest only when I’m reasonably confident that the test result would influence a treatment decision.

My impression is that, in general, oncologists’ habits of ordering routine, interval-based imaging for patients in remission after cancer treatment (such as a scan every 3 or 4 or 6 or 12 months) are arbitrary and unsupportable by any published data. These sorts of practices, which vary among communities, arise like this: A senior, smart and well-intentioned oncologist at a major teaching hospital, circa 1990, orders newfangled CT scans of the chest, abdomen and pelvis on his lymphoma patients every 4 months for two years, and then every 6 months for two years, and then every 12 months, for no reason other that he thinks it’s a good idea. The patients like it; they’re reassured, and he (the oncologist) feels good about having prescribed the drugs that caused their sustained remission.

Talk about a positive feedback loop! (We needn’t even invoke financial incentives as a motivating force.) And then that’s just how it’s done by all the fellows he’s taught over the years, who then branch out into other communities and even other countries, and teach…

Why not?

Now things may be changing a bit, as patients like me are starting to fear radiation exposure, and also are starting to question doctors’ recommendations more than they did even a few years ago. Younger doctors, too, have more requirements to continue their medical education in order to keep practicing at most hospitals and maintain their board certificates, and so they, too, may be more questioning of these archaic practices.

—

About post-treatment screening with scheduled blood work, I see this issue somewhat differently than do the NEJM authors, mainly in that I’m optimistic about simple blood tests, in the future, that may provide affordable and clinically relevant information to patients who’ve undergone treatment with tumors at high risk of recurrence.

As the authors point out, there are some old tests, such as CEA screening, that can be helpful in monitoring for recurrence in patients with a history of colon cancer. In general, blood tests are less dangerous and less expensive than imaging studies. Besides, in patients with aggressive tumors that might respond to new targeted drugs, tests that measure circulating tumor cells (CTCs) in small blood samples, and could assess cells for new mutations, at low costs in the future (not now), might render some blood tests useful and even cost-effective, in the future.

Finally, I’d like to throw in a concern I have about some clinical trials, in case any study designers or persuasive cancer IRB members happen to be reading this post:

Some of the clinical trials for new cancer drugs may require too many follow-up MRIs, CTs and other scans. Even if Pfizer or any other company foots the bill, by participating in the trials patients shouldn’t be subjected to excessive radiation or even just the unpleasantness and hassle of a said-to-be-safe test like an MRI. This pet peeve is especially concerning in some trials requiring multiple post-treatment PET scans, the most rad-intense of common imaging methods.

Annual direct costs for cancer care are projected to rise — from $104 billion in 20061 to over $173 billion in 2020 and beyond.2…Medical oncologists directly or indirectly control or influence the majority of cancer care costs, including the use and choice of drugs, the types of supportive care, the frequency of imaging, and the number and extent of hospitalizations…

The article responds, in part, to Dr. Howard Brody’s 2010 proposal that each medical specialty society find five ways to reduce waste in health care. The authors, from the Divisions of Hematology-Oncology and Palliative Care at Virginia Commonwealth University in Richmond VA, offer two lists:

The essay caught my attention because I do think it’s true that we need more well-trained specialists, as much as we need capable general physicians. Ultimately both are essential for delivery of high-quality care, and both are essential for reducing health care errors and costs.

Primary care physicians are invaluable. It’s these doctors who most-often establish rapport with patients over long periods of time, who earn their trust and, in case they should become very ill, hold their confidence on important decisions – like when and where to see a specialist and whether or not to seek more, or less, aggressive care. A well-educated, thoughtful family doctor or internist typically handles most common conditions: prophylactic care including vaccinations, weight management, high blood pressure, diabetes, straightforward infections – like bacterial pneumonia or UTIs, gout and other routine sorts of problems.

On the other hand, specialists can be lifesaving when highly-detailed expertise matters. There are limits to how much a general internist knows about chemotherapy, for example. Even within the field of medical oncology, a subspecialty of internal medicine, there are doctors who only see patients with particular kinds of cancers. When I had breast cancer, for example, I chose an oncologist whose practice consists almost entirely of patients with breast cancer and related diseases. If someone in my family has a lymphoma, I’d advise them to consult with someone who, for the most part, patients with lymphoma and similar disorders. Why? Because each of these cancers represent a complex group of malignancies, and successful therapy depends in part on the doctor’s familiarity with each of the specific subtypes and the relevant, current data for those. Treatment of lung cancer involves choosing among a different set of drugs than would be considered for brain or kidney cancer.

I mention oncology, here, because I’m most familiar with this field. But the same holds, for example, in the subspecialty of Infectious Diseases: knowing about all the new HIV drugs, in pregnant women, children and adults, involves a different set of knowledge than knowing about parasites in the tropics, and that differs from knowing about viral and other, unusual infections in patients are immunocompromised after kidney, heart or lung transplants.

In each of these settings, expertise can reduce errors – because specialists are more likely, in the first place, to establish a correct diagnosis and, next, to prescribe the right therapy based on the best evidence available.

The same holds for other medical specialties, apart from Internal Medicine. As I’ve described before, the radiologist who interpreted my routine mammogram and follow-up sono was a breast imaging specialist. The orthopedist who reconstructed my spine is a scoliosis spine surgeon. I am confident that I wouldn’t be here and feeling as well as I do if it weren’t for their expertise.

You could argue that it’s impossible to provide these kinds of sub-sub-specialists to people in rural areas, or that it’s too expensive, but I don’t think either of these factors should be limiting. To a large extent, experts might work with primary care providers and communicate with patients via Telemedicine and Skype-like technologies. As for surgical subspecialties, it may be that patients would find it worthwhile to travel to a regional center where a specialized procedure is done routinely, as opposed to having an operation in a local hospital where the doctors perform a certain kind of surgery – say a laparoscopic splenectomy, for example – only a few times each year.

There’s a tradeoff, as discussed in the NEJM piece, between increasing use of specialists and fragmentation of care. I think this concern is legitimate, based on my experiences practicing medicine and as a patient. But I do think we need specialists, and sub-specialists if we want doctors who can answer their patients’ questions, i.e. who really know what they’re doing.

I was a bit surprised that the article mentions a survey of physicians in which the majority of respondents reported that “professional image” was the primary reason for seeking subspecialty credentials. While this may be true, I don’t think doctors’ motivation matters in this. From the public’s perspective, what’s important is that hand surgeons know how to do hand surgery, and that a heart specialist knows how to interpret an echocardiogram, and that the hospitals where they work not let them practice if they’re not appropriately credentialed.

In cutting health care costs, or in trying to so, I don’t think it makes sense to reduce the number of physicians or to short-cut their educations by way of 3-year medical schools. Rather we need well-trained primary care doctors we can rely on, who know the limits of their knowledge as much as they understand medicine, and top-notch specialists, both.

The drug, Benlysta (belimumab), targets a molecule called BlyS (B-lymphocyte Stimulator). The newspapers uniformly emphasize that this drug marks some sort of triumph for Human Genome Sciences, a biotech company that first reported on BlyS in the journal Science way back in 1999. BlyS triggers B cells to produce antibodies that, in patients with lupus tend to bind and destroy their own cells’ needed machinery, causing various joint, lung, liver, kidney, brain, blood vessel and other sometimes life-threatening problems. So if and when Benlysta works, it probably does so by blocking aberrant, autoimmune B cell activity.

The papers don’t give a lot of details on the drug’s effectiveness, except that it appears to help roughly 1 in 11 patients and the main benefit may be that some lupus patients on Benlysta can reduce their use of steroids, which have long-term and toxic effects on many organs. The most recent, major medical publication on a trial on the drug came out in the Lancet, two weeks ago.

Some reported caveats are that the drug has not been adequately tested or approved for patients with severe kidney or neurological manifestations of the disease, and that its activity, marginal as it is, appears to be less in patients of African heritage based on trials completed thus far. Additional trials are in the works.

The drug is expensive, to the updated tune of $35,000 per year. According to the WSJ: “Estimates of how many Americans are affected range from 161,000 to 1.5 million.” (How’s that for a wide ballpark figure? – likely a function of how hard it is to define and establish diagnosis for this disease, which anticipates how hard it will be to measure this drug’s effects, see below.) The same Journalpiece says analysts expect the drug to become a blockbuster, with annual sales eventually topping $1 billion.

I’ve been intrigued by lupus ever since I was a second-year medical student, studying pathology before BlyS was discovered and monoclonal antibodies could be bulk-manufactured and tested in clinical trials. The disease’s name – from the Latin term for wolf, refers to the appearance of a facial rash that some patients develop.

Lupus can be scary to treat. One of my clearest late-night memories of my residency was when a 23 year old woman with lupus “rolled in,” as we would say, to the E.R. around 5:30 AM, as I was nearing the end of my then nearly-unrestricted shift. “We’ve got a sickie,” a nurse said as she roused me from my work on a hand-written note about someone else. The patient was dehydrated and gasping for air, and I remember having trouble getting her IV in, but somehow I did and she made it at least to the ICU.

From an immunologist’s perspective, it’s a fascinating condition because it flares and quiets – sometimes on its own – and affects different organs in distinct patterns among patients. The causes of lupus are likely varied. It may be that shutting down BlyS with an antibody is just a fancy and possibly more-targeted, less-toxic way of doing what steroids, like prednisone, do to B lymphocytes.

The problem I’d anticipate with the trials – carried out by my ever-patient, expert rheumatology colleagues – is that it’s sometimes hard to measure disease activity and responsiveness in lupus, apart from the kidney, because so many of the symptoms are subjective. And because the disease can affect so many organs, it’ll be hard to appreciate the drug’s toxicity, as apart from disease in itself.

According to the Washington Post coverage, the proposal comes from the United Network for Organ Sharing, a Richmond-based private non-profit group the federal government contracts for allocation of donated organs. From the Times piece:

Under the proposal, patients and kidneys would each be graded, and the healthiest and youngest 20 percent of patients and kidneys would be segregated into a separate pool so that the best kidneys would be given to patients with the longest life expectancies.

I have to admit, I’m glad to see these stories in the media. Any reasoned discussion of policy and reform requires frank talk on health care resources which, even in the best of economic times, are limited.

On Friday the New York Timesreported that surgeons are performing far too many open breast biopsies to evaluate abnormal mammogram results. A new American Journal of Surgeryarticle analyzed data for 172,342 outpatient breast biopsies in the state of Florida. The main finding is that between 2003 and 2008, surgeons performed open biopsies in an operating room – as opposed to less invasive, safer biopsies with needles – in 30 percent of women with abnormal breast images.

I was truly surprised by this should-be outdated statistic, which further tips the mammography math equation in favor or screening. These numbers matter, and should be based in modern medical practice.

When the Annals of Internal Medicinepublished the since-adjusted recommendations for breast cancer screening by mammography in November 2009, the stated considerations were not about dollars and cents – which were incalculable – but about the number of women needed to be screened to save one life, and the incidence of false positives which cause harm – worrying, needless biopsies, complications of procedures, overtreatment, etc.

In the context of the health care reform discussion, and considering our country’s out-of-the-sky-and-rising medical bills, some (hopefully) well-intentioned economists heard about those trumped-up mammography papers and concluded that we shouldn’t screen women under 50 for breast cancer because it’s harmful and, what’s more, we can’t keep paying for this sort of care because it’s not evidence-based.

Those conclusions were flawed, though, because the data in those papers were old, as I’ve written previously, and didn’t include studies of digital mammography – which is better for detecting cancer in younger women who tend to have denser breast tissue. In December 2009, I noted that it was unreasonable to consider the costs of open needle biopsies in O.R.’s in any calculation of the harms of mammography, as had the Annals authors, because those kinds of procedures are outdated, or so I thought they were.

It turns out I’ve been living, still, in an academic medical enclave. According to the Times‘ coverage by Denise Grady:

The reason for the overuse of open biopsies is not known. Researchers say the problem may occur because not all doctors keep up with medical advances and guidelines. But they also say that some surgeons keep doing open biopsies because needle biopsies are usually performed by radiologists. The surgeon would have to refer the patient to a radiologist, and lose the biopsy fee…

The Times article suggests this pattern of over-doing open-biopsies, as documented in Florida, likely reflects national tendencies, including variation among different types of practices – academic, hospital-based, etc.

According to the article published in the American Journal of Surgery, the costs of a core needle biopsy using imaging guidance is around $5,000, or – if a vacuum biopsy device is used, around $6,000; the costs of an open procedure in the O.R. run in the range of $11,000 or more. The Times article indicates that doctors’ fees for a needle procedure range from $750 to $1500, and for an open, surgical biopsy from $1,500 to $2,500. For a ballpark estimate of the cost difference, say a core needle procedure is $5,500 + $1,000 for the doctor’s fees – that’s ~$6,500; a surgical procedure is $11,000 + $2,000 for the surgeon’s fees – that’s $13,000, an easy double.

So let’s say, for the sake of future calculations on mammography, that 10 percent of breast biopsies really do need to take place in the O.R. (which is a generous over-estimate, I think it should be 5 percent or fewer). But if 10 percent need be in the O.R.: then 20 percent of breast biopsies in the U.S. each year – said in the surgery paper to be 1.6 million per year in the U.S. – are being performed through an unnecessary, costlier technique.

Let’s call it an even $2.1 billion, or $2 billion, we should shave off the collective amount we spend on mammography and appropriate follow-up. The last digit doesn’t matter; these are huge numbers. No wonder the Times put this story on the front page.

These results should be factored into any proper calculation of costs in breast cancer screening. Now add (or better, subtract) the implications of the findings of two weeks ago – that full lymph node dissection is usually not necessary in women, even if the sentinel node is found to be positive at the time of definitive surgery for what turns out to be a cancer.

What needs be reassessed by public health specialists and economists who weigh in on these issues – and please help me out here, Task Force members and Dartmouth friends, if you would, because your input affects public thinking and, ultimately, policy – are the legitimate costs of screening (every other year, as opposed to annually), doing needle biopsy procedures (instead of open biopsies) and reducing the costs and long-term complications of surgery by eliminating routine lymph node dissection from the equation.

And then we should assess those numbers relative to the costs of treating a woman with metastatic breast cancer, which still has not yet been determined.

From an article in today’s New York Times on hiring discrimination against people who smoke:

“There is nothing unique about smoking,” said Lewis Maltby, president of the Workrights Institute, who has lobbied vigorously against the practice. “The number of things that we all do privately that have negative impact on our health is endless. If it’s not smoking, it’s beer. If it’s not beer, it’s cheeseburgers. And what about your sex life?”

I think he’s right, more or less, in a slippery-slope sort of way, seriously –

Regular readers of this blog know that I’m not into rants. Complaining is rarely constructive, I know. But I spent the afternoon sorting through a 2-month stack of medical bills and correspondences related to those. Despite the fact that I consistently pay bills on time, we received threatening notices from local hospitals for payments they deemed late.

A perspective in this week’s NEJM considers the Emerging Importance of Patient Amenities in Patient Care. The trend is that more hospitals lure patients with hotel-like amenities: room service, magnificent views, massage therapy, family rooms and more. These services sound great, and by some measures can serve an institution’s bottom line more effectively than spending funds on top-notch specialists or state-of-the-art equipment.

Thinking back on the last time I visited someone at Sloan Kettering’s inpatient unit, and I meandered into the bright lounge on the 15th floor, stocked with books, games, videos and other signs of life, I thought how good it is for patients and their families to have a non-clinical area like this. The “extra” facility is privately-funded, although it does take up a relatively small bit of valuable New York City hospital space (what might otherwise be a research lab or a group of nice offices for physicians or, dare I say, social workers) seems wonderful.

If real health care isn’t an even-sum expense problem, I see no issue with this kind of hospital accoutrement. As for room service and ordering oatmeal for breakfast instead of institutional pancakes with a side of thawing orange “juice,” chicken salad sandwiches, fresh salads or broiled salmon instead of receiving glop on a tray, that’s potentially less wasteful and, depending on what you choose, healthier. As for yoga and meditation sessions, there’s rarely harm and, maybe occasionally, good (i.e. value).

But what if those resources draw funds away from necessary medicines, better software for safer CT scans and pharmacies, and hiring more doctors, nurses or aides? (I’ve never been in a hospital where the nurses weren’t short-staffed.) As for employees who clean – hospital floors, nursing stations, patients’ TV remotes, IV poles, computer station keyboards and everything else that’s imperfect and unsterile, they should get more funding, everywhere. Clerks and transport workers are frequent targets in hospital layoffs, but they’re needed just the same.

Two years ago when a family member was hospitalized, his doctor – a senior cardiologist – personally wheeled him in the stretcher from the x-ray area back to the emergency room bay where he waited for a room, so that he wouldn’t spend more than the half hour or so he’d already been in the hallway, after the film was taken, waiting for the escort service. What’s wrong is not so much that the physician helped with a menial task that isn’t his job; he’s a really nice and caring sort, and I believe he didn’t mind, really, except that he does have a wife and family at home who surely were waiting on that day.

The cardiologist might have used that time, instead, to examine more closely someone’s neck veins or heart sounds, or spent a few more minutes reading a journal article, which would make it more likely he’ll make the right recommendation to his patients about, say, a drug for congestive heart failure or a new blood thinner. We can’t short-change hospital workers in such a way that physicians fill in on ordinary tasks because there’s no one else to perform those, while patients get first-class meals and art classes to make them happier.

I’m reminded of boarding airplanes. I fly coach, and as I pass through the first class section I often think how nice it would be to sit in front and have pleasant flight personnel attend my every need to maximize my comfort during what’s typically a miserable trip. But then, I’d be paying perhaps $3,000 instead of $680 for the same flight.

As passengers, maybe we’re not so discerning about our pilots or the model of airbus as we should. A pleasant, cheery place isn’t always the safest.

…Why do amenities matter so much? Perhaps patients simply don’t understand clinical quality. Data on clinical quality are complex, multidimensional, and noisy, and they have only recently become systematically available to consumers. Consumers may be making choices on the basis of amenities because they are easier to understand.

The authors note the potential value of amenities in patients’ experiences and outcomes:

One could argue that they’re an important element of patient-centered care. If amenities create environments that patients, providers, and staff members prefer, then providers and staff members may give better care and service in those environments and patients may have better health outcomes.

Amenities are costly, but they attract patients:

… the value of amenities is important because our health care system currently pays for them. Under its prospective payment system… Each hospital receives the same amount of reimbursement for each patient with a given diagnosis and is free to decide what mix of resources to devote to clinical quality and what to spend on amenities. In our research, we found that improvements in amenities cost hospitals more than improvements in the quality of care, but improved amenities have a greater effect on hospital volume.

ML is excited upon reading the latest New England Journal of Medicine (NEJM) which she still receives in print. Today’s issue includes four articles, if you count the accompanying editorial, on an experimental pill for treating some forms of lung cancer and other tumor types with distinct genetic profiles.

The new drug, called crizotinib, is manufactured by Pfizer and targets cellular enzymes including ALK (anaplastic lymphoma kinase). Sound like a mouthful? Well, it turns out that ALK acts up in some cases of non-small-cell lung cancer – an old-fashioned, catch-all oncology term that refers to most types of lung cancer in the U.S. that, literally, don’t comprise cells that look small when examined with a microscope. This tumor category, which affects nearly 200,000 people in the U.S. each year, includes three main subtypes: adenocarcinoma – the kind of lung cancer most common in non-smokers, squamous cell carcinoma and what’s called (seriously) “large cell” lung cancer.

In approximately 5% of non-small-cell lung cancers the malignant cells have a particular chromosomal defect that renders them vulnerable to crizotinib: the gene encoding ALK, on the short arm of human chromosome 2 (2p) is rearranged nearby the gene encoding EML-4 (echinoderm microtubule-associated protein like 4), such that an abnormally active, fusion protein is active in the tumor cells. This hybrid gene product, the result of a particular chromosomal abnormality, is implicated in tumor cell growth and proliferation. Some of these and other investigators have previously demonstrated that crizotinib inhibits ALK activity in cells in vitro and in some animal models.

OK, so in the first of the NEJM papers*, 31 authors (including 16 in Boston, at Harvard affiliated-medical institutions and 5 based at Pfizer, in La Jolla, CA), report on the trial of 82 men and women with non-small-cell lung cancer who qualified for the study. All had “advanced” tumors, meaning tumors that couldn’t be removed surgically, and 94% had tried other treatments before starting crizotinib. Each enrolled patient had a chromosomal rearrangement, identified by a molecular FISH study, resulting in the EML-4-ALK fusion protein. After some initial phase I work to test tolerance to this new drug, the patients were prescribed 250 mg by mouth, twice daily.

The results were dramatic, as things go for clinical studies of advanced non-small-cell lung cancer: 57% of the subjects responded (partially in all but one apparent instance, meaning that the tumors shrank but didn’t disappear). In an additional 33% of patients enrolled, the disease stabilized (meaning that the tumors didn’t get significantly smaller, but stopped growing as they were before treatment). Upon 6 months of treatment, the probability of progression-free survival was estimated at 72%, but the median had not yet been reached.

According to the study authors, the drug was well-tolerated overall, and most of the patients elected to remain on treatment after completion of the planned protocol. Among the 82 patients, 34 reported “mild” visual disturbances, according to the authors: “the events were most frequently described as trails of light following objects moving relative to the observer, particularly noticed during changes in ambient lighting…” These were considered “Grade 1,” according to Table 2 in the paper. Grade 3 and 4 toxicities were few, and mainly included abnormal liver enzymes affecting 5 or 6% of the patients.

The second paper is a case report, astonishing firstly because there are 18 authors describing the drug’s activity in 2 patients, and secondly because of the interesting nature of the tumor described, a condition called inflammatory myofibroblastic tumor (IMT). I don’t think I’ve ever seen a case of this, either in real-life practice or in preparing for my oncology boards, so for now I’ll quote the paper and say that IMTs occur mainly in young people and consist of malignant myofibroblasts – cells that, when normal, usually form muscle and related soft tissue structures. The ALK gene is rearranged and abnormally expressed in about half of these tumors.

Summary of the second paper: the investigators tried crizotinib in 2 patients with difficult cases of chemo-refractory IMT. One, a 44 year old man with a distinct ALK abnormality who’d undergone extensive abdominal surgery and received multiple chemotherapies, responded fabulously. The other IMT patient, a 21 year old man without evidence for an ALK rearrangement, didn’t respond to the drug.

The third paper, by a Japanese group with a corresponding author based at Jichi Medical University in Tochigi, Japan, describes the development of two secondary, acquired and resistance-conferring mutations in ALK in one lung cancer patient who was taking crizotinib. Among other methods, they performed deep sequencing to check the ALK sequence in many of the patients’ cells, and then confirmed the presence of 2 (but not 3, as were found by this method) mutations using Sanger sequencing. They performed some neat PCR tricks to amplify DNA that was specific to the tumor’s EML4-ALK hybrid, and determined that the two de novo mutations within the tumor cells were mutually exclusive: the patient seems to have developed two resistant tumor clones while on treatment with the ALK inhibitor.

Finally there’s an editorial, by two molecular biologists, Drs. B. Hallberg and R. Palmer, based in Sweden’s Umeå University. This drug has a lot of potential, is the gist of it. ALK mutations don’t just occur in some lung tumors and IMTs, but also in some childhood tumors called neuroblastomas and, more than occasionally, in some anaplastic lymphomas.

I am aware, also, from the NCI’s website and by reading, including some of the above articles, that crizotinib has activity against some other kinases, including c-MET and other signaling receptor molecules, some of which are implicated in cancer growth.

I contacted Pfizer today, and a representative informed me by email that pricing for crizotinib has not yet been determined. I asked about FDA plans, and he wrote: “Pfizer plans to submit crizotinib (PF-02341066) data in the first half of next year to the U.S. Food and Drug Administration (FDA) for regulatory approval.”

Now, there are several ongoing clinical trials of this drug, some for patients with non-small-cell lung cancer and some for patients with other “ALK+” tumors, meaning cancers that bear a mutation in the ALK gene.

Why am I blogging about this drug, a pill, that works imperfectly in perhaps most of 5% of non-small-cell lung cancer patients and, maybe, in some other rare tumors? Because this is the future of oncology and, ultimately I think, will provide cost-effective medicine that’s based in evidence and science.

The key is that the investigators tried the experimental drug in lung cancer patients with a specific genetic profile, one that predicts a response to this agent. If, in 3 or 5 or 10 years we could sequence a patient’s tumor and check for specific mutations, we could give medications tailored to what they’ve got, and avoid treating them with drugs that are unlikely to work. This kind of approach should, if done properly, reduce the costs of cancer care, if the drugs are reasonably-priced.

How drugs like crizotinib could save money:

1. This drug is a pill; slash the costs of IVs, pumps, bags of saline, nurses to administer…

2. Don’t give it to patients without a relevant genetic mutation;

3. Monitor patients for resistance and stop giving drugs when they no longer help the individuals for whom their prescribed.

The opinion piece, published on Sept. 8, considers the controversy that surrounded last year’s U.S. Preventive Service Task Force recommendations for screening mammography in the context of broader issues. It contains some serious accusations:

“Advocates of breast-cancer screening, particularly breast radiologists, immediately took action, denouncing the panel’s statements as government rationing, suggesting that the panel members had ignored the medical evidence…

“…Although it is true that individual medical providers care deeply about their patients, the guild of health care professionals — including their specialty societies — has a primary responsibility to promote its members’ interests. Now, self-interest is not in itself a bad thing; indeed, it is a force for productivity and efficiency in a well-functioning market. But it is a fool’s dream to expect the guild…to compete on true value when the opportunity to inflate perceived value is readily available.

OK, readers, so how do I recommend we resolve this thorny issue?

Physicians should be on salaries, set in such a way that their earnings aren’t based on the procedures they order or perform. For example, I don’t think a surgeon should earn more money if he or she performs a greater number of biopsies or mastectomies, as opposed to spending time examining and speaking with patients who are contemplating those procedures. I don’t think an oncologist should earn more money by ordering or administering more infusions of chemotherapy, as opposed to recommending a “wait and watch” type approach, palliative care, or giving pills that are effective in some malignancies.

If physicians’ potential profit motive clouds the mammography debate, as the authors contend, that doesn’t mean that mammography is ineffective. Rather it signifies that doctors and scientists should analyze data and make clinical decisions in the absence of financial or other conflicts of interest.

If patients could know that their doctors don’t have a vested interest in mammograms, or any other test or procedure they might prescribe, they’d trust them more. It’s for this reason, above all, that we should disconnect doctors’ decisions from economic gain.